CN106905305B - Preparation method of engelizin - Google Patents
Preparation method of engelizin Download PDFInfo
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- CN106905305B CN106905305B CN201710070415.XA CN201710070415A CN106905305B CN 106905305 B CN106905305 B CN 106905305B CN 201710070415 A CN201710070415 A CN 201710070415A CN 106905305 B CN106905305 B CN 106905305B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a preparation method of engelizin, which comprises the following steps: 1) carrying out Grignard exchange reaction on the compound 5, and then reacting with a glucolactone derivative 6 to obtain a compound 7;
wherein X is bromine or iodine, LG is chlorine, bromine, mesyloxy or p-toluenesulfonyloxy, PG is acetyl, tert-butyryl or benzoyl; 2) deprotecting the compound 7 under the action of alkali to obtain a final product of the compound of formula 8 of empagliflozin;
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of an empagliflozin medicine for treating diabetes.
Background
Empagliflozin (Empagliflozin) is a selective oral SGLT-2 inhibitor developed by Boringer Vargahin in combination with Gift pharmaceuticals. The medicine is a medicine which can selectively inhibit reabsorption of filtered glucose by glomerular proximal tubules, enables excessive glucose to be discharged from urine and directly reduces blood sugar, is used for treating type II diabetes hyperglycemia, and has obvious curative effect, good safety and tolerance, approval of American FDA in 2014 and wide market prospect.
The name of engelia purification science is: (1S) -1, 5-anhydro-1-C- [ 4-chloro-3- [ [4- [ [ (3S) -tetrahydro-3-furanyl ] oxy ] phenyl ] methyl ] phenyl ] -D-glucitol of the formula:
PCT patent WO2006120208A discloses that the preparation of engelizin and its key intermediates is reported as follows:
at present, most domestic and foreign patents and documents adopt a similar method of the route, but the general route of the method is overlong, and the process cost is higher: fluorobenzene and benzoyl chloride derivatives are subjected to Friedel-crafts acylation reaction and then react with (S) -3-hydroxytetrahydrofuran, so that the steps are complicated, the route is low in efficiency; the addition reaction of the key intermediate and the TMS protected glucolactone requires strict low temperature, the yield is low, the selectivity is poor, and the product needs to be purified by introducing protecting groups such as acetyl and the like to improve the crystallinity of the product in the subsequent reaction, so that the process step is additionally added; the Grignard addition product needs to be reduced by triethylhydrosilane to eliminate benzyl methoxy, and the reaction operation and treatment difficulty is increased.
Chinese patent publication No. CN105399735A reports the following methods:
although the route improves the butt-joint reaction of a key intermediate and glucolactone, the pivalate derivative of the empagliflozin is obtained in one step, the experimental steps are greatly shortened, the halogen is directly removed by using n-butyl lithium, the requirements on the reaction temperature and the reaction conditions are high, the key raw materials are only limited to iodo matters, and the cost of the route is still high, so that a new synthesis method which is simpler and efficient still needs to be found.
The journal j. label company.radiopharmam.2014, page 687, reports the following synthetic route:
although the method is slightly short in route, Mitsunobu reaction is needed for butt joint of phenol and (R) -3-hydroxytetrahydrofuran to generate more urea compounds and triphenoxyphos, and the treatment after the reaction is troublesome and is not beneficial to process amplification; the method of the subsequent steps in the route is basically consistent with the patent, the selectivity and the yield are low, the route steps are complicated, and the overall efficiency is low. There is therefore still a need to find new synthesis methods which are simpler and more efficient.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a novel preparation method of the empagliflozin and the key intermediate thereof, and the method has the advantages of simple process route, low cost and suitability for industrial production.
In order to realize the purpose of the invention, the invention adopts the following technical scheme:
a preparation method of empagliflozin comprises the following steps:
1) carrying out Grignard exchange reaction on the compound 5, and then reacting with a glucolactone derivative 6 to obtain a compound 7;
wherein X is bromine or iodine, LG is chlorine, bromine, mesyloxy or p-toluenesulfonyloxy, PG is acetyl, tert-butyryl or benzoyl;
2) deprotecting the compound 7 under the action of alkali to obtain a final product of the compound of formula 8 of empagliflozin;
preferably, in the step 1), the grignard exchange reaction is performed by isopropyl magnesium chloride, cyclohexyl magnesium chloride or n-butyl magnesium chloride or a complex of isopropyl magnesium chloride, cyclohexyl magnesium chloride or n-butyl magnesium chloride and lithium chloride, or by butyl lithium or sec-butyl lithium reaction to directly remove halogen to obtain an aryl lithium reagent.
Preferably, after the compound 5 in the step 1) is subjected to Grignard exchange reaction, a ligand is selected or is not selected to react with the gluconolactone derivative 6 under the action of a catalyst to obtain a compound 7, wherein the catalyst is selected from ferric trichloride, ferric acetylacetonate, nickel dichloride, a nickel dichloride ethylene glycol complex or bis (triphenylphosphine) nickel dichloride; the ligand is selected from 1, 10-phenanthroline, 2, 6-bis [ (4S) - (-) -isopropyl-2-oxazoline-2-yl ] pyridine, triphenylphosphine, tricyclohexylphosphine, tri-tert-butylphosphine, 1 '-bis (diphenylphosphino) ferrocene (dppf) or 2-dicyclohexylphosphine-2', 6 '-dimethoxy-1, 1' -biphenyl (S-Phos); the reaction solvent is tetrahydrofuran, 2-methyltetrahydrofuran, toluene or dichloromethane and the like; the reaction temperature is generally-75 to 110 ℃.
Preferably, in the deprotection reaction of step 2), the base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium carbonate, or the like; the reaction solvent is selected from dichloromethane, 1, 2-dichloroethane, 1, 4-dioxane, toluene, acetone, methanol, ethanol, isopropanol or acetonitrile, etc.; the reaction temperature is-20 to 90 ℃.
The invention also relates to a preparation method of the key intermediate compound 5, which adopts the following technical scheme:
a process for the preparation of key intermediate compound 5 comprising the steps of:
1) carrying out Friedel-crafts acylation reaction on the 2-chloro-5-halogenated benzoic acid type 1 compound and phenol under the action of polyphosphoric acid to obtain a compound 2;
2) condensing the compound 2 and an R-3-substituted-tetrahydrofuran compound of formula 3 under an alkaline condition to obtain a compound 4;
wherein X is bromine or iodine, and Y is chlorine, bromine, iodine, methylsulfonyloxy, p-toluenesulfonyloxy;
3) carrying out reduction reaction on the compound 4 to obtain a compound 5;
wherein, X is bromine or iodine.
Preferably, the reaction temperature in the step 1) is 50-120 ℃.
Preferably, the condensation reaction base of step 2) is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, triethylamine or diisopropylethylamine; the reaction solvent is N, N-dimethylformamide, N-dimethylacetamide, acetonitrile, tetrahydrofuran, 1, 4-dioxane, toluene, isopropanol or acetone, and the reaction temperature is-10-110 ℃.
Preferably, the reducing agent in the reduction reaction in the step 3) is potassium borohydride; the additive is selected from aluminum chloride or trifluoroacetic acid; the reaction solvent is selected from dichloromethane, 1, 2-dichloroethane, toluene, tetrahydrofuran or 2-methyltetrahydrofuran; the reaction temperature is-10 to 80 ℃.
The invention relates to a preparation method of engletin, which comprises the steps of carrying out PPA acylation on 2-chloro-5-bromo/iodobenzoic acid 1 and phenol to obtain a compound 2, carrying out condensation reaction on the compound 2 and an R-3-halogenated tetrahydrofuran compound 3, and reducing by using potassium borohydride to obtain an engletin key intermediate compound 5; the glucose lactone derivative 6, reaction conditions, a catalyst and the like in the key Grignard docking reaction are optimized and screened, the Engelliforme hydroxyl protected derivative 7 which is easy to crystallize and purify can be obtained in one step, and finally, the Engelliforme product is obtained through simple deprotection. These improvements greatly improve the route efficiency and further reduce the process cost. The method has the advantages of simple operation, shortened reaction steps, high yield, high purity of the obtained product, and suitability for mass production.
Detailed Description
The following examples are given for the detailed implementation and specific operation of the present invention, but the scope of the present invention is not limited to the following examples.
Example 1
Adding polyphosphoric acid (94mL) into a three-neck flask, adding a compound shown as a formula 1a (23.55g,100mmol), heating to about 50 ℃ of internal temperature, uniformly stirring, adding phenol (18.82g,200mmol), heating to 80-85 ℃ after adding, reacting for 3-4 hours, cooling to 50 ℃ after reaction, slowly adding water (235mL) dropwise to quench the reaction, adding dichloromethane (141mL), stirring for 20 minutes, separating out an organic phase, extracting an aqueous phase for 2 times with dichloromethane (70mL), combining the organic phases, washing with a saturated sodium bicarbonate (141mL) solution, washing with a saturated saline (70mL) for 2 times, drying with sodium sulfate, concentrating, and recrystallizing with a dichloromethane-ethanol mixed solvent to obtain a compound 2a (27.11g, 87%). ESI M/z 311.0(M + 1).
Example 2
Polyphosphoric acid (113mL) is added into a three-neck flask, a compound shown as a formula 1b (28.25g,100mmol) is added, the mixture is heated to about 50 ℃ of internal temperature and stirred uniformly, phenol (18.82g,200mmol) is added, after the addition is finished, the temperature is raised to 80-85 ℃ for reaction for 3-4 hours, after the reaction is finished, water (283m) is slowly added dropwise to quench the reaction, dichloromethane (169mL) is added, the mixture is stirred for 20 minutes, an organic phase is separated, a water phase is extracted for 2 times by dichloromethane (84mL), a saturated sodium bicarbonate (169mL) solution of the organic phase is combined and washed for one time, a saturated saline (84mL) is washed for 2 times, sodium sulfate is dried, and the mixture is concentrated and recrystallized by a mixed solvent of dichloromethane and ethanol to obtain a compound 2b (29.76g, 83. ESI M/z 358.9(M + 1).
Example 3
A three-necked flask was charged with 2a (31.16g,100mmol), R-3-chloro-tetrahydrofuran (11.73g,110mmol), potassium carbonate (27.64g,200mmol), potassium iodide (830mg,5mmol) and acetonitrile (155mL), stirred well and then heated to 50-55 ℃ for reaction overnight. After completion of the reaction, the reaction mixture was directly concentrated to remove part of acetonitrile, water (155mL) and dichloromethane (155mL) were added, the aqueous phase was extracted with dichloromethane (78mL) again for 1 time, the organic phases were combined, washed with saturated brine for 1 time (155mL), dried over sodium sulfate, concentrated, and recrystallized from a mixed solvent of petroleum ether and ethyl acetate to give compound 4a (34.73g, 91%).
The potassium carbonate in example 3 can be replaced by sodium carbonate, cesium carbonate, potassium tert-butoxide, triethylamine or diisopropylethylamine; the acetonitrile solvent can be replaced by N, N-dimethylformamide, N-dimethylacetamide, tetrahydrofuran, 1, 4-dioxane, toluene, isopropanol or acetone.
Example 4
A three-necked flask was charged with 2b (35.86g,100mmol), R-3-p-toluenesulfonyloxytetrahydrofuran 3b (26.65g,110mmol), potassium carbonate (27.64g,200mmol), potassium iodide (830mg,5mmol) and acetonitrile (179mL), stirred well and heated to 50-55 ℃ for reaction overnight. After completion of the reaction, the reaction mixture was directly concentrated to remove part of acetonitrile, water (179mL) and dichloromethane (179mL) were added, the aqueous phase was extracted with dichloromethane (89mL) again for 1 time, the organic phases were combined, washed with saturated brine for 1 time (179mL), dried over sodium sulfate, concentrated, and recrystallized from a mixed solvent of petroleum ether and ethyl acetate to give compound 4b (37.29g, 87%).
The potassium carbonate in example 4 can be replaced by sodium carbonate, cesium carbonate, potassium tert-butoxide, triethylamine or diisopropylethylamine; the acetonitrile solvent can be replaced by N, N-dimethylformamide, N-dimethylacetamide, tetrahydrofuran, 1, 4-dioxane, toluene, isopropanol or acetone.
Example 5
Adding 4a (38.16g,100mmol) and tetrahydrofuran (304mL) into a three-neck flask, stirring uniformly, adding potassium borohydride (10.79g,200mmol), cooling to 0-5 ℃, adding aluminum trichloride (13.34g,100mmol) in batches, slowly raising the temperature to room temperature for 30 minutes after the addition is finished, and heating under reflux for reaction overnight. After the reaction was completed, the reaction was cooled to room temperature and quenched with 0.5mol/L dilute hydrochloric acid (190mL), the aqueous phase was extracted 2 times with ethyl acetate (190mL), the combined organic phases were washed 2 times with saturated brine (190mL), dried over sodium sulfate, concentrated and recrystallized from ethanol to give Compound 5a (30.88g, 84%).
The reaction solvent tetrahydrofuran in example 5 may be replaced with dichloromethane, 1, 2-dichloroethane, toluene or 2-methyltetrahydrofuran.
Example 6
4b (42.86g,100mmol) and tetrahydrofuran (342mL) are added into a three-neck flask, potassium borohydride (10.79g,200mmol) is added after uniform stirring, trifluoroacetic acid (11.40g,100mmol) is added in portions after cooling to 0-5 ℃, the temperature is slowly raised to room temperature for 30 minutes after the addition is finished, and the reaction is heated to reflux overnight. After the reaction was completed, the reaction was cooled to room temperature and quenched by addition of 0.5mol/L dilute hydrochloric acid (214mL), the aqueous phase was extracted 2 times with ethyl acetate (214mL), the combined organic phases were washed 2 times with saturated brine (214mL), dried over sodium sulfate, concentrated and recrystallized from ethanol to give Compound 5b (35.25g, 85%).
The reaction solvent tetrahydrofuran in example 6 may be replaced with dichloromethane, 1, 2-dichloroethane, toluene or 2-methyltetrahydrofuran.
Example 7
Adding a compound shown in the formula 5a (36.77g,100mmol) and tetrahydrofuran (184mL) into a three-neck flask, stirring and dissolving, cooling to-10-0 ℃ in an ice salt bath, switching nitrogen in vacuum for 3 times, dropwise adding 1.0M isopropyl magnesium chloride lithium chloride complex tetrahydrofuran solution (105mmol, 105mL), and reacting for 1-2 hours for later use under the condition of heat preservation. Adding the compound 6a (45.23g, 110mmol) and ferric acetylacetonate (1.77g,5.0mmol) into another reaction bottle, adding tetrahydrofuran (184mL) for dissolving under the protection of nitrogen, dripping the prepared Grignard reagent solution into the reaction bottle, heating to 40-50 ℃ for reacting for 6-8 hours, adding dilute hydrochloric acid (2mol/L,184mL) for quenching reaction after the reaction is finished, extracting the mixed solution with ethyl acetate (184mL) for 3 times, combining organic phases, washing with saturated common salt water for 2 times (184mL), drying with sodium sulfate, filtering, and recrystallizing with isopropanol to obtain 7a (40.24g, 65%).
In example 7, the Grignard exchange reaction using isopropyl magnesium chloride lithium chloride complex can be replaced by isopropyl magnesium chloride, cyclohexyl magnesium chloride or n-butyl magnesium chloride or their complex with lithium chloride, or butyl lithium and sec-butyl lithium reaction directly remove halogen to obtain aryl lithium reagent. The tetrahydrofuran solvent can be replaced by 2-methyltetrahydrofuran, toluene or dichloromethane, and the catalyst acetylacetone iron can be replaced by ferric trichloride, acetylacetone nickel, nickel dichloride glycol complex or bis (triphenylphosphine) nickel dichloride.
Example 8
Adding a compound shown in the formula 5a (36.77g,100mmol) and tetrahydrofuran (184mL) into a three-neck flask, stirring and dissolving, cooling to-10-0 ℃ in an ice salt bath, switching nitrogen in vacuum for 3 times, dropwise adding 1.0M isopropyl magnesium chloride lithium chloride complex tetrahydrofuran solution (105mmol, 105mL), stirring for 10-15 minutes, dropwise adding n-butyl lithium tetrahydrofuran solution, and keeping the temperature for reacting for 1-2 hours for later use. Adding the compound 6b (63.75g, 110mmol) and ferric acetylacetonate (1.77g,5.0mmol) into another reaction bottle, adding tetrahydrofuran (184mL) for dissolving under the protection of nitrogen, dropping the prepared Grignard reagent solution into the reaction bottle, heating to 40-50 ℃ for reacting for 6-8 hours, adding dilute hydrochloric acid (2mol/L,184mL) for quenching reaction after the reaction is finished, extracting the mixed solution with ethyl acetate (220mL) for 3 times, combining organic phases, washing with water for 2 times (184mL), drying with sodium sulfate, filtering, concentrating, and recrystallizing with ethyl acetate petroleum ether mixed solvent to obtain 7b (52.75g, 67%).
In example 8, the Grignard exchange reaction using isopropyl magnesium chloride lithium chloride complex can be replaced by isopropyl magnesium chloride, cyclohexyl magnesium chloride or n-butyl magnesium chloride or their complex with lithium chloride, or butyl lithium and sec-butyl lithium reaction directly remove halogen to obtain aryl lithium reagent. The tetrahydrofuran solvent can be replaced by 2-methyltetrahydrofuran, toluene or dichloromethane, and the catalyst acetylacetone iron can be replaced by ferric trichloride, acetylacetone nickel, nickel dichloride glycol complex or bis (triphenylphosphine) nickel dichloride.
Example 9
Adding the compound shown in the formula 5b (41.47g,100mmol) and tetrahydrofuran (207mL) into a three-neck flask, stirring and dissolving, cooling to-10-0 ℃ in an ice salt bath, switching nitrogen in vacuum for 3 times, dropwise adding 1.0M isopropyl magnesium chloride lithium chloride complex tetrahydrofuran solution (105mmol, 105mL), and reacting for 1-2 hours for later use under the condition of heat preservation. Adding a compound 6c (82.58g, 110mmol) and a nickel dichloride glycol complex (383mg,2.0mmol) into another reaction flask, adding tetrahydrofuran (207mL) into the 2, 6-bis [ (4S) - (-) -isopropyl-2-oxazoline-2-yl ] pyridine (PyBox,903mg,3mmol) under the protection of nitrogen for dissolving, dropping the prepared Grignard reagent solution into the reaction flask, heating to 40-50 ℃ for reacting for 6-8 hours, adding diluted hydrochloric acid (2mol/L,207mL) to quench the reaction after the reaction is finished, extracting the mixed solution for 3 times by using ethyl acetate (207mL), combining organic phase water for 2 times (207mL), drying by using sodium sulfate, filtering, concentrating, and recrystallizing by using ethyl acetate petroleum ether mixed solution to obtain 7c (63.32g, 73%).
In example 9, the Grignard exchange reaction using isopropyl magnesium chloride lithium chloride complex can be replaced by isopropyl magnesium chloride, cyclohexyl magnesium chloride or n-butyl magnesium chloride or their complex with lithium chloride, or butyl lithium and sec-butyl lithium reaction directly remove halogen to obtain aryl lithium reagent. The tetrahydrofuran solvent may be replaced by 2-methyl tetrahydrofuran, toluene or dichloromethane, and the catalyst nickel dichloride glycol complex may be replaced by ferric acetylacetonate, ferric trichloride, nickel acetylacetonate, nickel dichloride or bis (triphenylphosphine) nickel dichloride. The ligand 2, 6-bis [ (4S) - (-) -isopropyl-2-oxazoline-2-yl ] pyridine can be replaced by 1, 10-phenanthroline, triphenylphosphine, tricyclohexylphosphine, tri-tert-butylphosphine, 1 '-bis (diphenylphosphino) ferrocene (dppf) or 2-dicyclohexylphosphine-2', 6 '-dimethoxy-1, 1' -biphenyl (S-Phos).
Example 10
Adding the compound 7a (61.91g,100mmol) into a three-neck flask, adding tetrahydrofuran (301mL), stirring to dissolve, adding potassium carbonate (55.28g,400mmol), heating to 40-45 ℃ after adding, and reacting for 2-3 hours. After the reaction is finished, part of tetrahydrofuran is removed, water (301mL) is added after the reaction is cooled to room temperature, ethyl acetate (301mL) is added for extraction for 2 times, organic phases are combined, the organic phases are washed with saturated common salt water for 2 times (301mL), sodium sulfate is dried, the filtration is carried out, and the concentration is carried out, and then the recrystallization is carried out by using a mixed solvent of toluene and ethanol to obtain the product of the empagliflozin 8(41.93g, 93%).
Example 11
Adding the compound 7b (78.74g,100mmol) into a three-neck flask, adding absolute ethyl alcohol (236mL), stirring to dissolve, adding 20% lithium hydroxide aqueous solution (96g,800mmol), heating to 40-45 ℃ after adding, and reacting for 2-3 hours. After the reaction is finished, partial ethanol is removed, water (236mL) is added after the reaction is cooled to room temperature, ethyl acetate (236mL) is added for extraction for 2 times, organic phases are combined, the organic phases are washed with saturated common salt water for 2 times (236mL), dried by sodium sulfate, filtered, concentrated and recrystallized by using a mixed solvent of toluene and ethanol to obtain the product of the empagliflozin 8(39.23g, 87%).
Example 12
Adding the compound 7c (86.73g,100mmol) into a three-neck flask, adding tetrahydrofuran (433mL), stirring to dissolve, adding sodium methoxide (54g,1000mmol), heating to 40-45 ℃ after adding, and reacting for 2-3 hours. After the reaction is finished, tetrahydrofuran is removed by spinning, water (433mL) is added after the reaction is cooled to room temperature, ethyl acetate (433mL) is added for extraction for 2 times, organic phases are combined, the organic phases are washed with saturated common salt water for 2 times (433mL), dried by sodium sulfate, filtered, concentrated and recrystallized by using a mixed solvent of toluene and ethanol to obtain the product of the empagliflozin 8(40.58g, 90%).
Claims (5)
1. The preparation method of the empagliflozin is characterized by comprising the following steps:
1) after undergoing the Grignard exchange reaction, the compound 5 reacts with a glucolactone derivative 6 to obtain a compound 7;
wherein X is bromine, LG is chlorine, bromine, mesyloxy or p-toluenesulfonyloxy, PG is acetyl;
2) deprotecting the compound 7 under the action of alkali to obtain a final product of the compound of formula 8 of empagliflozin;
the Grignard exchange reaction in the step 1) adopts complex of isopropyl magnesium chloride, cyclohexyl magnesium chloride or n-butyl magnesium chloride and lithium chloride for Grignard exchange; after undergoing a Grignard exchange reaction, the compound 5 reacts with a gluconolactone derivative 6 under the action of a catalyst to obtain a compound 7, wherein the catalyst is selected from ferric trichloride or ferric acetylacetonate.
2. The method for preparing empagliflozin according to claim 1, characterized in that the reaction solvent in step 1) is tetrahydrofuran, 2-methyltetrahydrofuran, toluene or dichloromethane; the reaction temperature is-75-110 ℃.
3. The method for preparing empagliflozin according to claim 1, characterized in that the method for preparing the compound 5 comprises the following steps:
A) carrying out Friedel-crafts acylation reaction on the 2-chloro-5-bromobenzoic acid type 1 compound and phenol under the action of polyphosphoric acid to obtain a compound 2;
B) condensing the compound 2 and an R-3-substituted-tetrahydrofuran compound of formula 3 under an alkaline condition to obtain a compound 4;
wherein X is bromine, Y is chlorine, p-toluenesulfonyloxy;
C) carrying out reduction reaction on the compound 4 to obtain a compound 5;
wherein X is bromine.
4. The method for preparing empagliflozin according to claim 3, characterized in that the reaction temperature in the step A) is 50-120 ℃.
5. The process for preparing engagliflozin according to claim 3, characterized in that the condensation reaction base of step B) is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, triethylamine or diisopropylethylamine; the reaction solvent is N, N-dimethylformamide, N-dimethylacetamide, acetonitrile, tetrahydrofuran, 1, 4-dioxane, toluene, isopropanol or acetone, and the reaction temperature is-10-110 ℃.
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| CN113666892B (en) * | 2021-09-23 | 2023-08-15 | 浙江宏元药业股份有限公司 | New crystal form of englitz intermediate and preparation method thereof |
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| CN101193903A (en) * | 2005-05-10 | 2008-06-04 | 贝林格尔.英格海姆国际有限公司 | Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives and intermediates therein |
| CN105399735A (en) * | 2015-12-29 | 2016-03-16 | 上海应用技术学院 | Empagliflozin intermediate, and preparation method and application thereof |
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2017
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101193903A (en) * | 2005-05-10 | 2008-06-04 | 贝林格尔.英格海姆国际有限公司 | Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives and intermediates therein |
| CN105399735A (en) * | 2015-12-29 | 2016-03-16 | 上海应用技术学院 | Empagliflozin intermediate, and preparation method and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| Efficient Synthesis of Empagliflozin, an Inhibitor of SGLT-2, Utilizing an AlCl3-Promoted Silane Reduction of a β-Glycopyranoside;Xiao-jun Wang et al.;《Organic Letters》;20140725;第16卷;第4090-4093页 * |
| Stereoselective C-Glycosylation Reactions with Arylzinc Reagents;Sebastien Lemaire et al.;《Organic Letters》;20120302;第14卷(第6期);第1480-1483页 * |
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